1. Field of the Invention
This invention relates to pharmaceutical gallium compositions, particularly those having enhanced oral bioavailability relative to simple gallium salts and methods for their use. Gallium has demonstrated pharmaceutical value for the treatment of many human and animal disorders, including hypercalcemia, cancer, and especially certain widespread degenerative or metabolic bone diseases such as osteoporosis and Paget's disease.
2. References
The following references are cited in this application as superscript numbers at the relevant portion of the application:
1. Hart and Adamson, Proceedings of the National Academy of Sciences, U.S.A., 68:1623-1626 (1971) PA1 2. Collery, U.S. Pat. No. 4,596,710 PA1 3. Adamson et al., Chemotherapy Reports, 59:599-610 (1975) PA1 4. Warrell, Jr. et al., U.S. Pat. No. 4,529,593 PA1 5. Bockman et al., U.S. Pat. No. 4,704,277 PA1 6. Warrell, Jr. et al., "Gallium in the Treatment of Hypercalcemia and Bone Metastasis", in "Important Advances in Oncology 1989", DeVita, Jr., Editor, J. P. Lippincott Company, Philadelphia, Pa. PA1 7. Porter, "The Use of Opadry, Coateric, and Surelease in the Aqueous Film Coating of Pharmaceutical Oral Dosage Forms", at pp. 317-362 of "Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms", McGinity, Editor, Marcel Decker, Inc., New York, N.Y. (1989) PA1 8. Nagai et al., "Applications of HPMC and HPMCAS Aqueous Film Coatings of Pharmaceutical Dosage Forms", at pp. 81-152 of "Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms", McGinity, Editor, Marcel Decker, Inc., New York, N.Y. (1989) PA1 9. Jones, "Production of Enteric Coated Capsules", Manufacturing Chemist & Aerosol News, 41:43-57 (1970) PA1 10. Messora, U.S. Pat. No. 3,927,195 PA1 11. Porter, "Coating of Pharmaceutical Dosage Forms", at Chapter 91, pp. 1633-1643, of "Remington's Pharmaceutical Sciences", Gennaro et al., Editors, 17th Ed. (1985) PA1 12. Windholz et al., The Merck Index, 9th Edition, pp. 741-742, Merck & Company, Rahway, N.J. (1976) PA1 13. Foster et al., "Gallium Nitrate: The Second Metal With Clinical Activity", Cancer Treatment Reports, 70:1311-1319 (1986) PA1 14. Hider et al., U.S. Pat. No. 4,575,502 PA1 15. Finnegan et al., Inorganic Chemistry, 26:2171-2176 (1987) PA1 16. Farrar et al., Food and Chemical Toxicology, 26:523-525 (1988) PA1 17. Ott, International Journal of Artifical Organs, 6:173-175 (1983) PA1 (a) a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone wherein said 3-hydroxy-4-pyrone has the formula ##STR1## wherein each R is independently selected from the group consisting of hydrogen and alkyl of from 1 to 6 carbon atoms; and PA1 (b) means to inhibit dissociation of said complex under acidic conditions of the gastro portion of said gastrointestinal tract PA1 (a) a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone wherein said 3-hydroxy-4-pyrone has the formula ##STR2## wherein each R is independently selected from the group consisting of hydrogen, and alkyl of from 1 to 6 carbon atoms; and PA1 (b) means to inhibit dissociation of said complex under acidic conditions of the gastro portion of said gastrointestinal tract. PA1 employing in said composition a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone wherein said 3-hydroxy-4-pyrone has the formula: ##STR3## wherein each R is selected from the group consisting of hydrogen, and alkyl of from 1 to 6 carbon atoms; and PA1 further employing in said composition means to inhibit dissociation of said complex under acidic conditions of the gastro portion of said gastrointestinal tract. PA1 (a) a neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone wherein said 3-hydroxy-4-pyrone has the formula: ##STR4## wherein each R is independently selected from the group consisting of hydrogen, and alkyl of from 1 to 6 carbon atoms; and PA1 (b) means to inhibit dissociation of said complex under acidic conditions of the gastro portion of said gastrointestinal tract. PA1 The term "neutral 3:1 gallium complex of a 3-hydroxy-4-pyrone" refers to an electrostatically neutral complex of Ga.sup.+3 and 3 equivalents of the anionic form of 3-hydroxy-4-pyrone which complex is represented by the formula [Ga.sup.+3 (py.sup.-1).sub.3 ] wherein py.sup.-1 represents the anionic form of 3-hydroxy-4-pyrone which is defined below. Because such complexes do not dissociate to any significant extent in aqueous solutions maintained at a pH of from about 5 to about 9, these complexes remain predominantly electrostatically neutral in such solutions. PA1 (1) Addition of a sufficient amount of a pharmaceutically compatible buffering agent to the 3:1 complex that would bring the pH of the stomach fluids to a range of from about 5-9 and preferably from about 6-7 so that the stomach fluids would no longer disrupt the 3:1 hydroxypyrone:Ga complex. PA1 Pharmaceutically compatible buffering agents are those which, while acting as a buffering agent, do not significantly alter the ability of the neutral 3:1 gallium complex to deliver gallium to the bloodstream of the patient and are not toxic either alone or in combination with the neutral gallium complex. The particular pharmaceutically compatible buffering agent employed is not critical. Examples of preferred pharmaceutically compatible buffering agents include, by way of example, calcium carbonate (CaCO.sub.3), sodium bicarbonate (NaHCO.sub.3) and the like. On the other hand, aluminum hydroxide, Al(OH).sub.3, and other aluminum-containing compounds, by way of example, should be avoided. Other pharmaceutically compatible buffering agents are well own in the art and are recited in standard pharmaceutical manufacturing textbooks (e.g., Remington's Pharmaceutical Sciences by Mack Publishing Company). PA1 (2) Adding to the pharmaceutical composition containing the 3:1 complex an excess of free hydroxypyrone (or a salt thereof containing a physiologically acceptable cation), particularly the one used to make the 3:1 complex. Such a mixture, when dissolved in the stomach, has the effect of shifting the equilibrium among the 1:1, 2:1, and 3:1 complexes towards a preponderance of the 3:1 complex. In this embodiment, the weight of the free hydroxypyrone incorporated into the formulation is preferably 0.1 to 100 times the weight of the 3:1 complex employed in the formulation, and more preferably 0.1 to 10 times. This method, by itself, is not highly preferred but may be used in conjunction with other methods to inhibit dissociation. PA1 (3) Formulating the pharmaceutical composition that contains the 3:1 complex in delayed release form, so that a preponderance of the complex is not released until the intestinal tract is reached. An example of such a composition is to formulate the 3:1 complex with certain gels, preferably hydrogels such as a polymerized polyethylene glycol hydrogel, that adsorb the 3:1 complex and then release it after ingestion only very slowly while in the stomach. The preparation of such delayed release formulations, particularly those using hydrogels, is well known in the art. PA1 (4) Most preferably, formulating or packaging the 3:1 complex in such a way that the release of the 3:1 complex is prevented or inhibited until the basic, or less acidic, conditions of the intestinal tract are reached. Specific preferred methods include: PA1 .ANG.=.ANG.ngstrom PA1 C=Centigrade PA1 kg=kilogram PA1 M=Molar PA1 mg=milligram PA1 ml=milliliter PA1 mm=millimeter PA1 N=Normal PA1 nm=nanometers
The disclosures of each of these references are incorporated herein by reference in their entirety.